The objective of this Program Project Grant is to study the molecular neurobiological mechanisms underlying opiate and cocaine addiction. The program of research contains two major strengths. First, is the multidisciplinary nature of our ongoing and proposed research. Each research area represents an integration of molecular, biochemical, electrophysiological, neuropharmacological, and behavioral levels of analysis aimed at our basic research with a well-established clinical research program in drug abuse in our research group. The Program Project Grant is organized into a small Administrative Core, two scientific Cores, and five Projects. The transgenic Core is responsible for the breeding of may types of transgenic and knock out mice, and constructs for viral-mediated gene transfer, to be utilized in the proposed research. The Core is also responsible for the construction of several new lines of mutant mice, including those with inducible tissue-specific transgenes. The Behavioral Core is responsible for analysis of relatively routine drug-relative behaviors, including opiate withdrawal, locomotor activity, and place conditioning, in both rats and mice. Project 1 is a continuation of a productive and collaborative effort among several laboratories to study the molecular and cellular mechanisms by which opiates regulate locus coeruleus neurons and to relate these changes to behavioral measures of opiate withdrawal. Project 2 is a continuation of related collaborative studies that focus on molecular and cellular actions on opiates and cocaine in several other target brain regions, including dorsal raphe, prefrontal cortex, and lateral septum. Project 3 is a continuation of collaborative molecular, cellular, and behavioral studies of the role of specific neuropeptide receptors in the long-term actions of opiates and cocaine on specific target brain regions. Project 4 is a continuation of efforts to study the functional role by known molecular and cellular responses to drugs of abuse in the mesolimbic dopamine system. Animal models of drug reinforcement and craving, in conjunction with transgenic and viral-mediated gene transfer methods, will be used. Project 5 is a new effort to examine the genetic contributions to drug abuse in people. This work is an ideal way of applying fundamental knowledge arising from the basic Projects to clinical populations. Renewal of the Program Project Grant will enable continuation, and further strengthening, of our multidisciplinary research program into the molecular neurobiological mechanisms underlying drug addiction.